The objective of this research program is to develop powerful strategies and reactions to transform simple, commercially available compounds into structurally complex, nitrogen-containing molecules with high efficiency and in a practical fashion. By undertaking syntheses of biologically active alkaloids having a high level of architectural and/or stereochemical complexity, our ultimate goal is to extend the capabilities of chemical synthesis through the development of innovative strategies and efficient bond-forming reactions. The methods section of the research plan is divided into 5 parts. The first part describes the evolution of our design for synthesizing acutumine, a unique, chlorine-containing plant alkaloid that enhances memory in rats and inhibits human T-cell proliferation with moderate potency. The development of a 5-step synthesis of the complex molecular framework of acutumine will provide the foundation for an eventual total synthesis of this alkaloid and related nitrogen-containing compounds. The second part describes our effort to develop a concise synthesis of terpendole E featuring a novel cation-olefin cascade cyclization process. Terpendole E, a complex indole diterpene, is the only known natural product inhibitor of the motor activity of the human mitotic kinesin Eg5 and is a potential anti-cancer agent. Parts 3 and 4 describe our plans for developing unconventional photochemical cyclizations in the context of syntheses of the scarce, architecturally remarkable marine alkaloids chartelline A and chartellamide A. The final part describes our ongoing effort to develop metal-catalyzed, cis-selective chloroaminations of alkenes for use in a total synthesis of the potent immunosuppressive and cytotoxic alkaloid palau'amine. The structurally novel, biologically active alkaloids described in this grant application are attractive objectives for chemical research because successful strategies for their synthesis do not yet exist. These molecules provide rich opportunities to invent powerful strategies and broadly useful methods for complex chemical synthesis.